Ocular inflammation may take the form of numerous eye disorders of varying severity depending on the location of the inflammation. Disorders attributed to ocular inflammation include uveitis, conjunctivitis, episcleritis, scleritis, optic neuritis, retrobulbar neuritis, keratitis, blepharitis, and the like. Many of these conditions occur secondary to bacterial or viral infection.
In ocular bacterial infection, endotoxin (the lipopolysaccharide component of gram negative bacteria) produces ocular inflammation as indicated by conjunctival and iridial hyperemia, breakdown of blood aqueous barrier and polymorphonuclear neutrophil infiltration into the aqueous humor and iris ciliary body. In this type of inflammation, some of the arachidonic acid metabolites of the prostaglandins and leukotrienes have been implicated as inflammatory mediators. Other studies have also demonstrated that additional inflammation may be caused by the secondary induction of the expression of major histocompatibility complex Class II (1a) antigens in the iris ciliary body.
Ocular inflammation can also result following ophthalmologic surgical procedures or ocular trauma resulting from physical injury of the eye.
Uveitis is typical of these ocular disorders, and is characterized by inflammation of the uveal tract, which encompasses the iris, ciliary body, and choroid. Retinal inflammation is also classified as a type of uveitis. Uveitis may be anatomically classified as anterior (iritis and iridocyclitis), intermediate (cyclitis and peripheral uveitis), posterior (choroiditis and retinitis) and diffuse (iritis plus intermediate uveitis plus chorioretinitis). Merck Manual, 15th ed., 2227 (1987).
Repeated episodes of anterior uveitis, for example, can cause permanent and severe damage to the internal structures of the eye with grave consequences. For example, recurrent anterior uveitis may lead to the formation of considerable peripheral anterior synechia and secondary glaucoma. Chronic anterior uveitis can also cause corneal endothelial dysfunction and even cataract formation. Posterior inflammation can lead to persistent pathological vitreous alteration and retinal dysfunction, either of which may result in intractable visual loss.
It is well known that during acute and chronic inflammation various putative mediators of inflammation are released by the inflamed tissues and by leukocytes. The concentrations of these mediators and leukocytes are indicative of the level or degree of inflammation. Likewise, a reduction in concentration of these mediators and leukocytes is an indication of the effectiveness of a drug in treating inflammation.
Anti-inflammatory steroidal preparations (e.g., corticosteroids) are currently the drug of choice in the treatment of uveitis and other ocular inflammatory conditions. Although there is a wide range of other anti-inflammatory drugs available, only corticosteroids are presently approved for use ill the treatment of ocular inflammation.
The anti-inflammatory action of corticosteroids is thought to be due to interference with arachidonic acid metabolism, i.e., by inhibition of phospholipase A.sub.2 which causes the release of arachidonic acid from the tissue phospholipid pool. Although steroids are effective in the treatment of ocular inflammation, their extended use is complicated by severe and numerous side effects. Therefore, it would be highly desirable to develop new nonsteroidal drugs which have a high therapeutic effectiveness but which do not exhibit steroid-like side effects.
It has been previously demonstrated that dexamethasone (a corticosteroid), cyclosporin A (a potent immunosuppressive agent) and rapamycin (an antifungal and immunosuppressive agent) inhibited the corneal graft rejection process in the heterolammelar corneal transplantation model in the rabbit. Current Eye Res., 9:749-757 (1990). In this study, rapamycin was also found to be more potent than cyclosporin A in prolonging the graft survival after cessation of treatment.
Some preliminary clinical studies demonstrated that cyclosporin A may be effective in alleviating inflammatory symptoms in chronic idiopathic uveitis patients, some of whom were resistant to corticosteroid treatment. Am. J. Ophtal., 96:275-282 (1983); Lancet, 2:235-238 (1983). However, numerous cytotoxic side effects are observed with cyclosporin A, most likely due to the large doses of cyclosporin A required to obtain a therapeutic effect.
Accordingly, it is desirable to develop a treatment for ocular inflammation without the deleterious side effects of corticosteroids or cyclosporin A.
Rapamycin, a macrocyclic triene antibiotic produced by Streptomyces hygroscopicus, and described in U.S. Pat. No. 3,929,992, incorporated herein by reference, has been shown to prevent the formation of humoral (IgE-like) antibodies in response to an albumin allergic challenge [Martel, R., Can. J. Physiol. Pharm. 55:48 (1977)], inhibit murine T-cell activation [Strauch, M., FASEB 3:3411 (1989)], and prolong survival time of organ grafts in histoincompatable rodents [Morris, R., Med. Sci. Res. 17:877 (1989)].